In spite of all the advances in molecular medicine, malaria still afflicts about 300 million people worldwide and half of the world population is at rik. The disease causes nearly million deaths each year, mostly children. Unfortunately, the prospects for control of malaria by chemotherapy have been seriously compromised by the emergence of resistance to all available drugs. Most of the current malaria therapeutics was developed more than 30 years ago and many are derived from older chemotypes. Given the severity of the global malaria situation, it is extremely urgent to identify potent and safe chemicl entities with antimalarial activity that are structurally distinct from existing antimalarials. The proposed phase I STTR research project, which is a partnership between Smart Biomolecules Inc., and the University of Central Florida, seeks to discover and further develop novel antimalarial scaffolds through screening of the Torrey Pines Institute for Molecular Studies (TPIMS) proprietary high-density combinatorial libraries containing of over 30 million compounds. Because the TPIMS compound libraries occupy underrepresented areas of chemical space and have large degree of molecular complexity, we hypothesize that the proposed studies will identify novel pharmacophores, thus contributing significantly to the malaria elimination campaign. Arrangement of the libraries in the scaffold ranking and positional scanning formats will enable us to screen the entire collection very rapidly. Our preliminary work has identified novel scaffolds from the piperazine-tethered thiazole library to possess potent and selective anti-plasmodial activity. To accomplish our objective to identify leads for malaria therapy from this series of compounds, we propose to: (a) Deconvolute the piperazine-tethered thiazole library to identify selective lead compounds and (b) Determine development stage-specific action and resistance potential; (3) Evaluate the in vivo efficacy of piperazine-tethered thiazole lead compounds.